One-pot synthesis of alkyl 3-cyclopropylamino -2-[2,4-dibromo-3-(difluromethoxy) benzoyl]-2-propenoate as a useful intermediate for antibacterial quinolone medicaments

ABSTRACT

The present invention relates to a new and industrially advantageous one-pot process for the preparation of alkyl 3-cyclopropyl amino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoates of in which R represents methyl or ethyl, which are valuable intermediates for the production of highly active antibacterial quinolone medicaments.

FIELD OF THE INVENTION

[0001] The present invention relates to a new and industriallyadvantageous one-pot process for the preparation of alkyl 3-cyclopropylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoates in whichR represents methyl or ethyl, which are valuable intermediates for theproduction of highly active antibacterial quinolone medicaments.

BACKGROUND OF THE INVENTION

[0002] A previously known general method for the synthesis ofintermediate, alkyl 3-cyclopropylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoate of thefollowing formula:

[0003] has been reported in U.S. Pat. No. 5,935,952 assigned to ToyamaChemical Company Ltd. The general method described in this patentincludes, reaction of the compound of the following formula:

[0004] with a halogenating agent such as thionyl chloride to obtain acidchloride of the following formula:

[0005] which on reaction with metal salt of malonic ester of thefollowing formula:

Na/KOOCCH₂COOR   Formula IV

[0006] wherein R is the same as defined above, in the presence ofmagnesium chloride at a temperature of about 45° C. Decarboxylation ofFormula IV affords a compound of the following formula:

[0007] in which R is as defined above. Reaction of the compound ofFormula V with an acetal such as N,N-dimethylformamide dimethyl acetal,N,N-dimethylformamide diethyl acetal to give a compound of the followingformula:

[0008] wherein R₁ is methyl or ethyl, which on reaction withcyclopropylamine gives the intermediate, methyl/ethyl 3-cyclopropylamino-2-[2,4-dibromo-3-(difluoro-methoxy)benzoyl]-2-propenoate, ofFormula I.

[0009] The above mentioned method described in the prior art for themanufacture of the compound of Formula I suffers from the followinglimitations and for various reasons stated below are not suitable forcommercial purposes.

[0010] The process is lengthy involving six steps.

[0011] The process generates a lot of effluent waste and hence is noteco-friendly.

SUMMARY OF THE INVENTION

[0012] It is an object of the present invention to solve the problemsassociated with the prior art and to provide an efficient method.

[0013] According to one aspect of the present invention there isprovided a one-pot process for the preparation of alkyl3-cyclopropylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoateof Formula I. The process provides obvious benefits with respect toeconomics and convenience to operate at a commercial scale.

[0014] More particularly, the present invention relates to a process forthepreparationofalkyl3-cyclopropylamino-2-[2,4-dibromo-3-dfluoromethoxy)benzoyl]-2-propenoateof Formula I, wherein R is methyl or ethyl comprising reacting2,4-dibromo-3-(difluoromethoxy)benzoic acid of Formula II, with ahalogenating agent to get a corresponding acid chloride of Formula III,which on reaction with ester of 3,3-dialkyl amino acrylate of thefollowing formula:

[0015] wherein R₁ is methyl or ethyl, in a suitable solvent in thepresence of an organic base to givealkyl-3,3-dialkylamino-2[2,4-dibromo-3-difluoromethoxy)benzoyl]-2-ropenoateof Formula VI wherein R and R₁ are methyl or ethyl which on treatmentwith cyclopropylamine affords the product of Formula I, and R is thesame as defined above. More particularly, the compound of Formula II isreacted with thionyl chloride to provide an acid chloride of Formula IIIfollowing a process known in the prior art. The acid chloride is thenreacted with methyl/ethyl ester of 3,3-dimethyl/diethylamino acrylate ofFormula VI (R and R₁ are methyl or ethyl) in a suitable solvent in thepresence of an organic base at a selected temperature within the rangeof 40-80° C., preferably, 50-70° C. during a period of one to severalhours. The suitable solvent is selected from the group comprising ofaromatic solvents, chlorinated solvents ester solvents and mixture(s)thereof. Preferably, the solvents are selected from the group comprisingbenzene, toluene, xylenes, chloroform, dichloroethane, dichloromethanemethyl acetate, butyl acetate, ethyl acetate or mixture(s) thereof. Thesuitable organic base is selected from the group comprisingtriethylamine, trimethyl amine, picolines, pyridine and pyridinederivatives. The reaction mixture is then cooled and poured into water.The organic layer contains the compound of Formula VI wherein R₁ ismethyl or ethyl and is taken as such for reaction with cyclopropylamineat a selected temperature within the range of 0-30° C., preferably 5-10°C. for 0.5 to several hours. The desired compound methyl/ethyl3-cyclopropylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoateof Formula I is isolated by conventional methods.

[0016] In the following section a preferred embodiment is described byway of an example to illustrate the process of this invention. However,this is not intended in any way to limit the scope of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 Preparation ofEthyl-3-cyclopropylamino-2-(2,4-dibromo-3-difluoromethoxy)benzoyl]-2-propenoate

[0017] To a mixture of 2,4-dibromo-3-(difluoromethoxy)benzoic acid (10g) and thionyl chloride (4.38 gm) was added a mixture of toluene (15 ml)and N,N-dimethyl formamide (0.2 ml). The reaction mixture was heatedslowly to reflux and stirred at reflux for about 2.5 hours. The reactionmixture was then cooled to 35° C. and added a solution of ethyl3,3-dimethylaminoacrylate (4.13 gm), and triethylamine (3.79 gm) intoluene (20 ml) drop-wise during a period of about 1 hour maintaining atemperature of 35-40° C. After the addition was over, the reactiontemperature was slowly increased to 60-65° C. and stirred the reactionmixture for about 24 hours. Cooled the reaction mixture to 30° C., addedwater (20 ml) and stirred for about 10 minutes. The organic layer wasseparated, cooled to about 5° C. and cyclopropylamine (1.82 gm) wasadded to it drop-wise maintaining temperature at 8-10° C. during aperiod of about 10 minutes. Stirred the reaction mixture for about 2hours, solvent was removed under vacuum (˜80% of the original amount)and cooled the reaction mixture to about 20° C. The solid separated wasfiltered and dried to afford ethyl3-cyclopropylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoate(10 gm).

[0018] While the present invention has been described in terms of itsspecific embodiments, certain modifications and equivalents will beapparent to those skilled in the art and are intended to be includedwithin the scope of the present invention.

EXAMPLE 2 Preparation of ethyl3-cyclopropylamino-2-[2,4-dibromo-3-(difuluoromethoxy)benzoyl]-2-propenoate

[0019] To a mixture of 2,4-dibromo-3-(difluoromethoxy)benzoic acid (50g) in ethyl acetate (175 mL) was added N,N-dimethyl formamide (1 mL) andthionyl chloride (18.1 g). The reaction mixture was heated to reflux andstirred at reflux for 1 hr. After evaporation of ethyl acetate, (125mL), triethylamine (16.1 g) and ethyl 3,3-dimethylaminoacrylate (20.7 g)were added to the reaction mixture at room temperature. This reactionmixture was heated to reflux and stirred at reflux for 3 hrs. Themixture was then cooled to 25° C., water (100 mL) was added and themixture was stirred for about 10 minutes. The organic layer wasseparated and cyclopropylamine (9.9 g) was added to it and the reactionmixture was stirred at 25° C. for 1 hr. The solvent of the reactionmixture was exchanged by isopropanol (200 mL), maintaining thetemperature about 68° C. The crystallization was achieved by cooling ofthe mixture, followed by filtration, washing with isopropanol and dryingto affordethyl3-cyclopropylamino-2-[2,4-dibromo-3-(difuluoromethoxy)benzoyl]-2-propenoate(58.6 g).

We claim:
 1. A process for the preparation of alkyl3-cyclopropylamino-2-[2-4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoateof the following formula:

wherein R is methyl or ethyl, comprising reacting2,4-dibromo-3-(difluoromethoxy)benzoic acid of the following formula:

with a halogenating agent to get a corresponding acid chloride of thefollowing formula:

which on reaction with alkyl ester of 3,3-dialkyl amino acrylate of thefollowing formula:

wherein R₁ is methyl or ethyl in a suitable solvent in the presence ofan organic base, to give alkyl3,3-dialkylamino-2-[2,4-dibromo-3-(difluoromethoxy)benzoyl]-2-propenoateof the following formula:

wherein R and R₁ are methyl or ethyl wherein R and R₁ are the same asdefined above, which on treatment with cyclopropylamine affords theproduct of Formula I.
 2. The process of claim 1 wherein the halogenatingagent is thionyl chloride.
 3. The process of claim 1 wherein the alkylester of 3,3-dialkylaminoacrylate is methyl ester of3,3-dimethylaminoacrylate.
 4. The process of claim 1 wherein the alkylester of 3,3-dialkylamino acrylate is ethyl ester of 3,3-diethylaminoacrylate.
 5. The process of claim 1 wherein the solvent is selected froma group comprising aromatic solvents, chlorinated solvents, estersolvents and mixture(s) thereof.
 6. The process of claim 5 wherein asolvent is selected from the group comprising benzene, toluene, xylenes,chloroform, dichloromethane, dichloroethane methyl acetate, butylacetate, ethyl acetate and mixture(s) thereof.
 7. The process of claim 1wherein the organic base is selected from the group comprisingtriethylamine, trimethylamine, picoline(s), pyridine and pyridinederivatives.
 8. The process of claim 1 wherein the reaction temperatureis in the range of 40-80° C.
 9. The process of claim 8 wherein thereaction temperature is in the range of 50-70° C.
 10. Use of thecompound of Formula I prepared by the process of claim 1 for thesynthesis of quinolone medicaments.